Project summary/Abstract Glaucoma is the second leading cause of blindness worldwide. The prevalence of this age-related disease is expected to increase substantially in coming years because of the aging population. Currently, the only clinically approved glaucoma intervention targets at lowering intraocular pressure (IOP). However, the exact roles of IOP elevation in glaucomatous pathogenesis remain unclear. In addition, glaucoma may continue to progress in some patients even after lowering IOP to normal levels, which indicates that additional key factors may be contributing to the disease. The goal of this project is to better understand glaucoma mechanisms by determining non-invasively and quantitatively the pathophysiological events and disease progression in the visual system using novel, multi-parametric magnetic resonance imaging (MRI) techniques in both human glaucoma patients and experimental glaucoma models. We will test the central hypothesis that glaucoma involves impairments of the brain's visual system apart from the eye. Furthermore, such impairments may be ameliorated by early neuroprotective treatments. We will investigate the structural, metabolic and functional brain changes longitudinally using the 3-Tesla human MRI scanner and the 9.4-Tesla animal MRI scanner, and relate brain MRI findings with glaucoma disease severity using retinal thickness measurements and visual outcome assessments. The project?s primary objective is to use the developed in vivo imaging model system to find out the structural-metabolic-functional brain relationships and eye-brain-behavior relationships in both humans and animal models of glaucoma for clinical and translational applications. This information will be valuable for identifying glaucoma mechanisms in the brain, monitoring glaucoma progression in the visual system, and guiding interventions to the visual system, in order to reduce the burden of this irreversible but preventable disease. The Specific Aims to be tested are as follows: Aim 1: To test the hypothesis that experimental glaucoma impairs the visual system and visuomotor behavior in rodents. We will elevate IOP to different levels and durations to determine their contributions to the structure, metabolism and function of the visual system. We will also determine whether oral choline supplements can ameliorate the neurobehavioral effects of experimental glaucoma on the visual system. Lastly, we will determine the specificity of glaucomatous damages to the visual system by comparing the neurobehavioral effects between experimental glaucoma and other retinal or optic nerve injuries over time. Aim 2: To test the hypothesis that vision loss in human glaucoma involves impairments of the visual system. Diffusion tensor MRI, proton MR spectroscopy and functional MRI at 3 Tesla will be used to determine the structural, metabolic and functional brain changes in glaucoma patients with different degrees of vision loss. The in vivo brain MRI measures will be compared with clinical assessments by optical coherence tomography of the retina and Humphrey visual field functional tests. The visual system in glaucoma will also be compared with healthy control brains and other retinal or optic nerve injuries.